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VOICE stands for “Vaginal and Oral Interventions to Control the Epidemic.” The VOICE study, also known as MTN-003, is a large, Phase IIb clinical trial originally designed to determine whether drugs used to treat HIV infection can also prevent male-to-female HIV transmission when used daily. The study, which is being carried out among HIV-negative women in three African countries, was originally designed to test the safety and effectiveness of two HIV prevention strategies: an investigational vaginal microbicide gel containing the antiretroviral drug tenofovir (1 percent concentration), and oral tablets containing tenofovir or a combination of tenofovir and another antiretroviral drug, emtricitabine. Taking the tablets daily to try to prevent HIV infection is a strategy known as oral pre-exposure prophylaxis, or PrEP.

On September 16, 2011, a routine review by an independent data and safety monitoring board (DSMB) found that the VOICE study would be unable to show a difference between tenofovir tablets and placebo tablets in their effectiveness at preventing HIV infection in the study participants. Consequently, the DSMB recommended that the trial discontinue testing oral tenofovir. For more information about this change, please see the answer to question 14 below.

In another scheduled review on November 17, 2011, the DSMB found that tenofovir gel was ineffective at preventing HIV infection in VOICE study participants. The DSMB therefore recommended that the trial also discontinue testing tenofovir gel. For more information about this change, please see the answer to question 15 below.

What is a microbicide?

A microbicide is designed to prevent HIV infection when applied topically inside the vagina or the rectum in the form of a gel, film or ring. No microbicide has been approved for use outside of research studies.

In July 2010, the CAPRISA 004 study found that a vaginal microbicide gel demonstrated a 39 percent level of efficacy at preventing HIV infection. The microbicide tested in that study contained the antiretroviral drug tenofovir at a concentration of 1 percent--the same as in the VOICE study. Study participants applied the microbicide before and after sex.

In the VOICE study, the microbicide was applied once daily.

What is oral PrEP?

Oral PrEP is an investigational strategy to prevent HIV infection by giving a daily oral dose of one or two antiretroviral drugs to HIV-negative people who are at risk for becoming infected. Scientists theorize that taking an antiretroviral drug before exposure to HIV could potentially inhibit HIV replication immediately after exposure to the virus, thereby thwarting the establishment of permanent infection.

In November 2010, the NIAID-sponsored iPrEx study demonstrated the safety and effectiveness of oral tablets containing combination tenofovir and emtricitabine at preventing HIV infection in men who have sex with men and in transgender women who have sex with men. In July 2011, two PrEP studies demonstrated the safety and effectiveness of both oral tenofovir and oral tenofovir/emtricitabine at preventing HIV infection in heterosexual men and women.

Who is participating in the VOICE study, and where is it being conducted?

The study team has enrolled 5,029 sexually active, HIV-uninfected women ages 18 to 45 into the clinical trial, which is taking place at 15 sites in South Africa, Uganda and Zimbabwe.

Who is funding the VOICE study?

The National Institute of Allergy and Infectious Diseases (NIAID) is sponsoring and funding the VOICE study with co-funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and the National Institute of Mental Health (NIMH), all part of the U.S. National Institutes of Health. The co-sponsors are CONRAD of Arlington, Va., and Gilead Sciences Inc. of Foster City, Calif.

Gilead Sciences is providing tenofovir and tenofovir/emtricitabine tablets to the VOICE study team free of charge, and CONRAD is providing tenofovir gel and gel applicators. Oral tenofovir is known by the brand name Viread. Co-formulated tenofovir/emtricitabine is known by the brand name Truvada.

Leading the VOICE study are protocol co-chairs Zvavahera Mike Chirenje, M.D., F.C.R.O.G., of the University of Zimbabwe in Harare, and Jeanne Marrazzo, M.D., M.P.H., of the University of Washington in Seattle.

When did the VOICE study begin? When are results expected?

The VOICE study began in September 2009, and results are expected in early 2013.

Which microbicide and oral PrEP regimens were originally being tested in the VOICE study, and what is being tested now?

The VOICE study originally was testing the safety and effectiveness of an investigational microbicide gel containing the antiretroviral drug tenofovir at a concentration of 1 percent. In addition, the study originally was testing the safety and efficacy of two oral PrEP regimens: a daily dose of 300 mg tenofovir, and a daily dose of 300 mg tenofovir plus 200 mg emtricitabine combined into one pill.

Investigators stopped testing oral tenofovir in September 2011 and stopped testing tenofovir gel in November 2011 following decisions by NIAID to accept the recommendations of an independent DSMB. For more information about these changes to the study, please see the answers to questions 14 and 15 below.

Why is the VOICE study important?

The VOICE study is important for several reasons. First, an effective microbicide or oral PrEP regimen could give women an HIV prevention method they control. This would be particularly helpful in situations where it is difficult or impossible for women to refuse sex or to negotiate condom use with their male partners. Women make up slightly more than half of all people worldwide living with HIV, and in sub-Saharan Africa, women represent nearly 60 percent of adults living with the virus. In most cases, women become infected with HIV through sex with an infected male partner.

In addition, if a regimen under study in VOICE is found to be effective, it could expand the number of HIV prevention tools available to curb the HIV/AIDS pandemic. The best offense against HIV infection is a comprehensive prevention toolkit that can be tailored to meet the needs of specific populations.

How does the VOICE study differ from other clinical trials of microbicides or oral PrEP?

The VOICE study is the first to test the effectiveness of a microbicide gel that women apply once daily rather than shortly before or after they have sexual intercourse. It is also one of the first large-scale clinical trials of the newer class of microbicides that contain an antiretroviral drug and thus act specifically against HIV.

The VOICE study also is the first to test a microbicide and oral PrEP in the same clinical trial. This approach aimed to enable researchers to directly compare the safety, effectiveness and acceptability of the two experimental HIV prevention strategies in adult heterosexual women. The study also is examining whether the antiretroviral drug-containing prevention strategies generate drug resistance, and if so, to what extent.

What is the study design?

VOICE was originally designed as a Phase IIb, five-arm, multi-site, placebo-controlled trial. Participants were assigned at random to one of five regimens, each performed once daily:

applying tenofovir gel vaginally

applying a placebo gel vaginally

taking a tenofovir pill and a placebo pill

taking a tenofovir/emtricitabine (Truvada) pill and a placebo pill

taking two placebo pills

In addition to testing tenofovir gel and oral PrEP for safety and effectiveness, the VOICE study aimed to determine which regimen—pill or gel—women were likely to follow more consistently and whether either intervention influences the risk-taking behavior of participants. The study also is assessing how frequently participants who acquire HIV during the trial develop resistance to tenofovir or to tenofovir/emtricitabine.

Study staff are following each participant for 14 to 36 months. At study visits, all participants receive HIV tests and risk-reduction counseling, condoms and testing for sexually transmitted infections. Any participant who acquires HIV or a sexually transmitted infection during the study is referred to appropriate treatment and care in her community.

How is the safety of the VOICE study participants protected? Safety is monitored closely throughout the study. Designed according to the most rigorous standards of international medical practice and ethics, the VOICE study contains numerous measures, beginning at the site level, intended to protect the safety and well-being of participants. These include a multi-tiered safety review process with strict U.S. and international procedures for monitoring and reporting of adverse events.

What is a DSMB, and what is its role in the VOICE study?

A DSMB is an independent group composed of clinical research experts, statisticians, ethicists and community representatives that meets at regular intervals during the study to review data as it is gathered. (The study team does not have access to pivotal study data until the clinical trial ends.) The DSMB alerts the study team if anything appears to compromise the safety of study participants, if there is compelling evidence of effectiveness, or if it becomes clear that the study cannot answer one of the questions it was designed to address.

The NIAID Prevention Trials DSMB regularly reviews the data from the VOICE study and has conducted six reviews to date. The November 17, 2011, meeting of the DSMB was the fifth interim review of safety data and the third of effectiveness data. The first DSMB review examined the study design before the clinical trial began.

Why did the study team stop testing oral tenofovir?

During a routine review of the VOICE study data on September 16, 2011, the DSMB found that the trial would be unable to show a significant difference between tenofovir tablets and placebo tablets in their ability to prevent HIV infection in study participants. (This situation is known as “futility” in the context of a clinical trial.) As a result of this finding, the DSMB recommended that the study discontinue evaluating tenofovir tablets while continuing to evaluate tenofovir gel and tenofovir/emtricitabine tablets as designed. Notably, the DSMB found no safety concerns with any study product.

NIAID concurred with the DSMB’s recommendations.

To protect the integrity of the ongoing clinical trial, the study data remain confidential to everyone except the DSMB until the study ends. Until that time, NIAID will not know or speculate about why oral tenofovir showed no effect among the VOICE study participants.

Why did the study team stop testing tenofovir gel?

During a planned interim review of the VOICE study data on November 17, 2011, the DSMB found that tenofovir gel was ineffective at preventing HIV infection among VOICE study participants. The rate of new HIV infections was the same (6 percent) in the group that applied the placebo gel daily as in the group that applied the tenofovir gel daily. Consequently, the DSMB recommended that the study discontinue evaluating tenofovir gel while continuing to evaluate tenofovir/emtricitabine tablets as designed. Notably, the DSMB found no safety concerns with any study product.

NIAID concurred with the DSMB’s recommendations.

To protect the integrity of the ongoing clinical trial, the study data continue to remain confidential to everyone except the DSMB until the study ends. Until that time, NIAID will not know or speculate about why tenofovir gel was ineffective in the VOICE study.

What happened to the study participants who had been taking oral tenofovir, applying tenofovir gel or applying placebo gel?

After the September 2011 DSMB meeting, the study team informed all study participants that oral tenofovir was being discontinued. Participants who had been randomly assigned to take the tenofovir tablets—roughly, 1,000 women—stopped using the product at their next scheduled clinic visit. Eight weeks later (in early December), they will return for a final set of tests and procedures, including HIV testing and counseling, before exiting the study. During this last study visit, the participants will receive information about where they can obtain HIV testing and counseling, contraception and other medical and support services as needed.

The study team is following the same procedures to inform all VOICE participants of the most recent development and to discontinue the tenofovir gel and placebo gel arms of the trial, which together involved roughly 2,000 women.

The women in the oral tenofovir and tenofovir gel groups who became HIV-infected and/or pregnant while participating in VOICE may continue to participate in MTN ancillary studies for those conditions (MTN 015 for those who acquired HIV infection during the VOICE study; MTN 016 for those who became pregnant).

How will the investigators know whether oral Truvada is effective at preventing HIV infection?Once the investigators have collected all the study data, they will compare the number of women in each group who acquire HIV through exposure in their environment during the study to determine whether the oral Truvada regimen is significantly more effective than the oral placebo regimen in preventing HIV infection.

How and why is bone density being studied in VOICE?

In previous animal studies of tenofovir, very high doses of the drug (many times higher than the dose given to humans) were found to have an adverse effect on the animals’ bone health. In addition, an ongoing clinical study of HIV-infected men and women taking tenofovir as part of an antiretroviral drug treatment regimen has found measurable decreases in the density of spine and hip bones. Thus, the VOICE study investigators want to learn what effects, if any, oral tenofovir has on the bone density of healthy, HIV-uninfected women.

About 500 study participants who were originally assigned to take the tenofovir or the tenofovir/emtricitabine tablets at sites in Uganda and Zimbabwe have enrolled in a sub-study called VOICE B. The VOICE B participants are periodically undergoing specialized testing of bone-mineral density so investigators can monitor the bone health of these trial volunteers even more closely. Once they finish participating in VOICE, the women enrolled in VOICE B will be offered an opportunity to have their bone density checked 6 and 12 months after they stop taking their VOICE study product.

What impact, if any, will the VOICE findings have on NIAID’s other oral tenofovir and/or tenofovir-based microbicide research?NIAID, its NIH partners and the MTN are considering the VOICE findings to date and how they may impact other tenofovir research studies that are in progress or in the planning stages. Each study will be examined in light of the new findings, with final decisions about the effect on each of these studies expected at a later time.

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